title: Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease.
abstract: BACKGROUND
  Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions.
  
  
  RESULTS
  Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A.
  
  
  CONCLUSIONS
  Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease.
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas CSIC-UAM, Arturo Duperier, 4 and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Morales-Garcia
authors.forename: Miriam
authors.initials: M
authors.lastname: Redondo
authors.forename: Sandra
authors.initials: S
authors.lastname: Alonso-Gil
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.forename: Concepción
authors.initials: C
authors.lastname: Perez
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Angel
authors.initials: A
authors.lastname: Santos
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Castillo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012377:Rodentia
chemical_list: D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D004298:Dopamine